CD4+ helper T-cell differentiate into at this time at least five well-defined subsets: Th0, Th1, Th2, Treg, Th17, and T follicular helper that can both promote and inhibit the behavior of each other. Recently, attention has been directed at the subset of CD4+,CD25+ T cells that express high levels of the winged fork head transcription factor, FoxP3. This subset strictly limits their own expression of proliferative cytokines and is generally incapable of producing growth cytokines such as IL-2 and IL-4. These cells have been shown to impair the activation of other conventional CD4+ T cells when the cells are in close proximity which could be important during autoimmune reactions; hence these cells are called T regulatory (Treg) cells. Despite a great deal of investigation, it is still unclear by what molecular mechanisms Treg cells are capable of suppressing other subsets of T cells and what role they play in normal immune reactions. For this reason, we considered the hypothesis that Treg cells, which are presently thought to be a stable lineage of cells that plays an active suppressive role in the maintenance of immunological self-tolerance and immune homeostasis, might also have an importantrole in protective immunity. The suppressive functions are exhibited in Foxp3-deficient mice and the human immune dysregulation enteropathy polyendocrinopathy X-linked (IPEX) syndrome patients that succumb to fatal inflammatory disorders associated with fewer numbers of Treg cellsdelete. Interestingly, although IPEX patients manifest apparent autoimmune diseases, they also have a susceptibility to specific infectious diseases, notably Candida albicans infections, suggesting selective immunodeficiencydelete. The transcriptional repressive effects of the forkhead box P3 (Foxp3) protein render Treg cells incapable of producing certain key cytokines such as interleukin-2 (IL-2) and so they require an exogenous supply of these cytokines for their peripheral maintenance. Indeed, Treg cells compete for IL-2 and other survival cytokines, leading to cytokine deprivation apoptosis of effector T cells. Careful experimental modeling of the cytokine competition mechanism of suppression by Treg cells reveals that suppression depends strongly on the local cytokine milieu and the proximity of Treg cells to effector cells during an immune response. Treg cells may not effectively suppress by cytokine competition when cytokines are abundant such as during an infection. Some studies have predicted that Treg cells could lose their suppressive functions during acute inflammation in microbial infection models. Plasticity of Treg cells and their potential nonsuppressive immune functions have been the recent focus of discussion. Importantly, certain investigations have demonstrated protective functions for Treg cells during viral infections. Thus, Treg cells may have broader roles in immunity than just the previously recognized suppressor functions. T helper 17 (Th17) cells produce abundant inflammatory cytokines and are key mediators in host defense, inflammatory disorders, and autoimmune conditions. Mechanisms of interactions between Treg cells and Th17 cells and the paradoxical ability of Treg cells to augment IL-17A induction are not well understood in vivo. One of the most important functions of Th17 cells in host immunity is to protect against fungal infections. Oropharyngeal candidiasis or thrush, an acquired immune deficiency syndrome-defining illness, is an infection by the commensal fungus C. albicans. It has been well documented in mice and humans that Th17 cells and IL-17 production are critical for oral fungicidal immune responses by recruiting neutrophils to the oral mucosa and inducing salivary antimicrobial factors. Patients with hyper-IgE syndrome with fingernail candidiasis or chronic mucocutaneous candidiasis have impaired Th17 cell responses. Interestingly, patients lacking Treg cells, including IPEX patients, those with IPEX-like syndrome (CD25-deficient patients) or autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED) patients deficient in the autoimmune regulator (AIRE) protein, also are highly susceptible to C. albicans infections. The underlying mechanism and possible roles of Treg cell deficiency in this susceptibility are unclear. In 2012, we investigated the function of Treg cells in modulating Th17 cell responses in an oral C. albicans infection model. Here we showed that Treg cells can powerfully promote the transition of naive CD4 cells to Th17 cells producing the full suite of characteristic cytokines independently of the effect mediated by transforming growth factor (TGF)-beta;. Treg cells achieved this by consuming IL-2 and thereby preventing it from inhibiting Th17 cell differentiation both in vitro and in vivo. Treg cells did not suppress, but actually promoted, IL-17A-dependent clearance of fungi during acute C. albicans infection. However, despite contributing potently to this acute immunoprotective effect, Treg cells exhibited suppressive properties at late times and inhibited chronic Th17 cell-mediated inflammatory bowel disease (IBD). Thus, we provide insights into a facet of Treg cell biology and that, in addition to immune suppression, they promote Th17 cell differentiation and participate in host protective immunity against fungal infections such as by C. albicans. Inflammatory bowel disease (IBD), which is generally thought to develop from a dysregulated immune response to the gut luminal biota, includes two major forms: Crohns disease (CD) and ulcerative colitis. Both genetic and environmental factors contribute to the development of CD1. Genome-wide association studies (GWAS) for Crohns disease have identified over 40 susceptibility loci. The large number of susceptibility genes likely reflects the complexity of the inflammatory process taking place along the gastrointestinal tract in IBD. The lymphoid tissue within the gastrointestinal tract constantly encounters commensal microbiota as well as potentially pathogenic bacteria; hence, it is critical to maintain a delicate balance between immune responsiveness and tolerance at this location. Research on susceptibility genes identified by GWAS has exemplified this concept, and yielded important insights into the pathogenesis of IBD. Leucine rich repeat kinase 2 (LRRK2) was recently identified in genome-wide association studies (GWAS) as a major susceptibility gene for Crohns disease (CD). LRRK2 is a 2527 amino acid predominantly cytoplasmic protein (286 kDa) containing several functional domains, including leucine-rich repeats (LRR), a Ras of complex proteins (ROC) domain, a C-terminal of ROC (COR) domain, a kinase domain and a WD40 repeat (WD) domain. LRRK2 was identified as the most frequently mutated gene in autosomal dominant familial Parkinsons disease (PD), but its pathological functions in that context are not well-understood. In 2012, we found that LRRK2 deficiency confers enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 is a potent negative regulator of the transcription factor NFAT and a component of the complex involving a non-coding RNA repressor of NFAT (NRON). Correspondingly, the risk-associated allele Met2397 identified in CD GWAS causes a post-translational reduction in LRRK2 protein. Severe colitis in LRRK2-deficient mice is associated with enhanced NFAT1 nuclear localization. Thus, our study defines a new step in the control of NFAT activation that involves an immunoregulatory function of LRRK2 and has important implications for inflammatory bowel disease. Ongoing collaborations with investigators in NINDS are directed at understanding the role of LRRK2 in Parkinson's disease in light of our immunological discoveries.